The proposed research in this NCI Outstanding Investigator Grant includes a description of ongoing projects funded through CA-30349 and CA-35318 and a new project entitled "Template directed design synthesis of novel DNA reactive drugs." The overall objectives of the proposed research are to: (1) provide a new rationale for the development of more clinically effective antitumor drugs, (2) rationalize the biochemical and biological effects of DNA modification on the basis of the effects of drug-binding on the structural and dynamic properties of DNA. The specific objectives of the proposed research are to: (1) determine the effects of drug-binding on local DNA structure and dynamics, (2) determine the structural and/or dynamic features which lead to repair recognition of damaged DNA, (3) determine the effect of drug binding on transcriptional control in eucaryotic systems, (4) isolate and identify novel drug receptors, and (5) design and synthesize new DNA-reactive drugs using a DNA template directed approach. States simply, the overall problem we propose to tackle is to elucidate the molecular basis for the antitumor activity of CC-1065 and the P(1,4)Bs. This problem is broad in context and requires an interdisciplinary approach, using a variety of physical and biochemical techniques. A central theme of our studies aimed towards determining the molecular basis for antitumor activity of CC-1065 and the P(1,4)Bs is to relate the structural changes in local DNA structure induced or entrapped by these drugs to the biochemical and biological effects. One aspect of the proposed work is to determine drug- related changes in DNA structure and relate these to the observed asymmetric effects on DNA structure, the origin of drug induced bending in DNA, and the molecular basis for the DNA sequence specificity of these agents. Further studies are proposed to identify DNA binding proteins involved in mediating the potent biological effects of the compounds.